Poxviruses express several different classes of immune modulators that suppress the host response to infection, including soluble cytokine binding proteins, serpins, chemokine binding proteins, a complement control protein, and members of the semaphorin and Toll/IL-1 receptor families. Biochemical activity of these proteins has been demonstrated by many in vitro studies. Conservation in evolution of poxvirus immune modulators implies that these genes are functional in vivo, but the results of infecting animals with knockout viruses have not always been clear cut. Studies involving different animal models are reviewed, and the criteria for suitable models are discussed. Challenges include finding an appropriate animal host, and using an inoculation route that resembles the process of natural infection. The fact that multiple immune modulators can target the same pathway at different steps may explain why single knockout mutants are not always attenuated in animals.